HIGHLIGHTS
• Germline alteration prevalence in predisposition genes is assessed in lung cancer patients from two large populations.
• Pathogenic/Likely Pathogenic alterations are found in genes like MUTYH, BRCA1, BRCA2, CHEK2 and ATM.
• Germline testing in lung cancer patients may enhance primary cancer prevention and screening of family members.

ABSTRACT
Background – Germline alterations and smoking status in lung cancer could inform etiology and clinical decisions. We explored germline alteration prevalence in predisposition genes across lung cancer histologies from two large populations.

Methods – Germline sequencing of 11,740 primary lung cancers was performed with Tempus xT tumor-normal matched assay (DNAseq of 648 genes at average 500x coverage, normal specimens at 150x coverage, full transcriptome RNA-seq). Pathogenic/likely pathogenic (P/LP) potential germline alterations in 46 genes were compared between smokers and never smokers; never smokers somatic EGFR altered (sEGFRalt) and wild-type (sEGFRwt); non-small cell (NSCLC) and small cell (SCLC) histologies; and NSCLC sEGFRalt and NSCLC sEGFRwt. P/LP variants were investigated in these 46 genes in 1,330 patients with lung cancer from the UK BioBank by smoking status.

Findings – Tempus sequencing revealed P/LP alterations in 4·8% of smokers and 5·8% of never smokers, with most alterations in MUTYH (1·3% vs. 1·1%), ATM (0·7% vs. 1·0%), BRCA2 (0·6% vs. 0·9%) and EGFR (< 0·1% vs. 0·4%). Never-smoker sEGFRalt (n=549) and sEGFRwt (n=1025) tumors had alterations in MUTYH (1·1% vs. 1·1%), ATM (0·7% vs. 1·1%), and EGFR (1·1% vs. 0%). NSCLC and SCLC tumors had alterations in MUTYH (1·3% vs. 0·3%), ATM (0·8% vs. 0·3%), and BRCA2 (0·7% vs. 0%). sEGFRalt and sEGFRwt NSCLC tumors had germline alterations in MUTYH (1·6% vs 1·3%), ATM (0·5% vs. 0·8%), EGFR (1·3% vs. 0%), and BRCA2 (0·8% vs. 0·6%). UK Biobank patients had similar P/LP alterations: 4·3% of smokers and 5·1% of never-smokers, with most germline alterations in ATM (0·8%), BRCA2 (0·79%) and MUTYH (0·62%) in smokers and MUTYH (1·5%) and CHEK2 (1·01%) in never-smokers.

Interpretation – Similar distribution of P/LP potential germline alterations in lung cancer subtypes from distinct populations by smoking status suggests increased next-generation germline sequencing may improve risk assessment.

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